Glaucoma is the second leading cause of blindness in the United States. Understanding how retinal ganglion cell (RGC) susceptibility to degeneration is modulated by the major risk factor, elevation of intraocular pressure (IOP), as well as other factors, will help in designing novel therapeutic approaches to complement IOP lowering. By studying experimental models of glaucoma and optic nerve injury, we and others have determined some of the cellular and gene expression alterations associated with the pathogenesis of glaucomatous RGC death. Among the genes whose expression is dysregulated, Neuritin1 (Nrn1) encodes a secreted factor that possesses strong neuroprotective and neurite-promoting activities on RGCs. We hypothesize that NRN1 is a novel RGC-derived neurotrophic factor whose IOP elevation- triggered downregulation in RGCs is associated with the onset and progression of RGC death in glaucoma. In this study, the therapeutic value of Nrn1 in RGC neuroprotection and axon regeneration will be evaluated with animal models of optic nerve stress. In aim1, we will assess whether Nrn1 is required for the maintenance of adult RGCs and their axonal network, whether Nrn1 can protect RGC from IOP elevation- induced degeneration, and whether it can promote RGC axon regeneration when the optic nerve is damaged. In aim2, we will focus on elucidating how Nrn1 expression is regulated by upstream signal pathway(s) and transcription factors. Moreover, the importance of these regulatory mechanisms in maintaining RGC survival will be evaluated. In aim3, we will explore the involvement of specific kinase(s) in the signal transduction of NRN1 in RGCs. By accomplishing the above proposed studies, we hope to gain insight into how impaired Nrn1 expression contributes to RGC degeneration and whether NRN1 could serve as a target for the development of novel neuroprotective strategies for the treatment of glaucoma and other optic neuropathies. PUBLIC HEALTH RELEVANCE: The goal of this project is to understand how retinal ganglion cells, the cells in the eye that transmit information from the eye to the brain, die in the disease glaucoma. We will specifically focus on the factor neuritin-1. Understanding neuritin-1's role in glaucoma may provide insights into the mechanisms of the disease, and may help to develop new treatment approaches to complement the traditional approach of eye pressure lowering.